This invention relates to 2H-phthalazin-1-one derivatives and poly (ADP-ribose) polymerase inhibitors containing 2H-phthalazin-1-one derivatives as active ingredient.
More particularly, this invention relates to poly (ADP-ribose) polymerase inhibitors containing 2H-phthalazin-1-one derivatives of the formula (I) 
(wherein all symbols are as hereinafter defined) and non-toxic salts thereof as active ingredient, novel 2H-phthalazin-1-one derivatives of the formula (Ia) as hereinafter defined and non-toxic salts thereof, and processes for the preparation thereof.
Poly(ADP-ribose)polymerase (abbreviated as PARP hereinafter) is a nuclear enzyme activated by DNA strand breaks, which play an important role the reaction that transfer of the ADP-ribose moiety from nicotinamide adenine dinucleotide (abbreviated as AND+ hereinafter) to various proteins such as histones, DNA-polymerases and DNA-topoisomerases, etc. DNA strand breaks is caused by Peroxynitrite (ONOOxe2x88x92) and oxygen radicals that leads to overactivation of PARP. (PARP on Zn finger domain binds to DNA with nicks and then PARP is activated up to 100 times.) Overactivation of PARP elicits depletion of AND+ which essential of electron transport and then ATP depletion leads to disturbance of energy production system, consequently cause to cell death. (The suicide theory of PARP activation: Free Radic. Biol. Med., 21, 855 (1996); TIPS., 19, 287 (1998)). Therefore, it is considered that PARP inhibitor may be useful as inhibition of cell death. Since caspase-3, one of interleukin-1xcex2-converting enzyme family, specifically cleaves PARP as the substrate, it is suggested PARP is associated with apoptosis. (Cell., 81, 801 (1995).
It is reported that 3-aminobenzamide and nicotinamide generally known as inhibitors of PARP are useful for inhibition of cell death and improvement of diseases on various models of ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis or arthritis etc.), diabetes, shock, extrapyramidal disease (TIPS., 19, 287 (1998); Eur. J. Pharmacol., 350, 1 (1998)) and hyperalgesia (Pain, 72, 355 (1997)) in vitro, in vivo and in the knockout mouse. And it is known they are increased the effects of antiretroviral (HIV etc.) (Biochem. Biophys. Res. Commum., 180, 504 (1991)) or anticancer drugs. (Radiat. Res., 126, 367 (1991); Br. J. Cancer., 72, 849 (1995)).
PARP inhibitor may be useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis or arthritis etc.), neurodegenerative disorders (extrapyramidal disease, Alzheimer""s disease or muscular dystrophy etc.), diabetes, shock, head trauma, renal insufficiency or hyperalgesia etc. And it may be increased the effects of antiretroviral (HIV etc.) or anticancer drugs.
For example, it is disclosed in JP kokai hei 2-124874 that the compound of formula (A) 
(wherein RA is OR1A, lower alkyl, NR1AR2A, a halogen, trifluoromethyl, C(O)X2A, CN, COX2A (wherein X2A is lower alkyl, aryl, or aralkyl), R1A is a hydrogen, lower alkyl, benzyl, etc., R2A is a hydrogen, lower alkyl, phenyl or benzyl, ZA is (i) xe2x80x94CHR2ACHR3Axe2x80x94 (wherein R3A is a hydrogen, alkyl, phenyl or benzyl), (ii) xe2x80x94CR5Axe2x95x90CR3A, or (iii) xe2x80x94CR3Axe2x95x90Nxe2x80x94 (when ZA is (iii), then N of ZA binds to N of ring), R3A is a hydrogen, lower alkyl, phenyl or benzyl, R5A is a hydrogen, lower alkyl, phenyl, benzyl, chlorine, bromine or NR7AR8A (wherein R7A and R8A each, independently, is a hydrogen or lower alkyl)) have an inhibitory activity on PARP (with the proviso that, definitions not related are omitted).
It is disclosed in SU 1378303 that the compound of formula (B) 
and it is not disclosed about the biological activity.
It is disclosed in JP kokai sho 57-167974 that the compound of formula (C) 
(wherein R2c and R3c each, independently, is C1-5 alkyl, C1-5 alkoxy, a halogen, C2-6 alkoxycarbonyl, carboxy, cyano, C2-4 alkylcarbonyl, hydroxy or trifluoromethyl, mC and nC is 0-3) is an intermediate of platelet aggregate inhibitor.
It is disclosed in JP kokai sho 54-032489 that the compound of formula (D) 
(wherein RD is hydroxy, methoxy or protected hydroxy) is an intermediate of antihypertensive.
It is disclosed in EP 534443 that the compound of formula (E) 
(wherein AE is C3-6 alkyl, C5-7 cycloalkyl, phenyl, thienyl, furyl, thiazolyl, phenoxy, C7-9 phenylalkyl, phenylthio, azacycloalkyl, pyridyl or imidazolyl, all of which may be substituted by C1-4 alkyl, C1-4 alkoxy and/or halogen; ring CE is benzene, furan or thiophene, all of which may be subsituted by C1-4 alkyl)
is an intermediate of platelet aggregate inhibitor.
It is disclosed in WO 9911624 that the compound of formula (F) 
(wherein XF is double-bonded oxygen or OH; R7F when present, is hydrogen or lower alkyl; YF represents the atoms necessary to form a fused mono-, bi- or tricyclic, carbocyclic or heterocyclic ring, wherein each individual ring has 5-6 ring member atoms; ZF is (i) xe2x80x94CHR2FCHR3Fxe2x80x94 (R2F and R3F are independently hydrogen, alkyl, aryl, aralkyl); (ii) xe2x80x94R6FFCxe2x95x90CR3Fxe2x80x94 (R3F and R6F are independently hydrogen, lower alkyl, aryl, aralkyl, halo, nitro, xe2x80x94COOR7F, xe2x80x94NR7FR8F where R8F is independently hydrogen or C1-9 alkyl, or R6F and R3F, taken together, form a fused aromatic ring, wherein each individual ring has 5-6 ring members); (iii) xe2x80x94R2FCxe2x95x90Nxe2x80x94; (iv) xe2x80x94CR2F(OH)xe2x80x94NR7Fxe2x80x94, (v) xe2x80x94(C(O)NR7Fxe2x80x94 or (vi) xe2x80x94NR9Fxe2x80x94C(O)xe2x80x94CHR10Fxe2x80x94 (R9F and R10F are independently hydrogen or lower alkyl, etc.),wherein said alkyl,aryl and aralkyl , are substituted at one or more positions with hydrogen, hydroxy, halo, haloalkyl, alkoxy, alkenyloxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, sulfhydryl, thioalkyl, carboxy, carbocycle, heterocycle, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitroso, dimethylamino) have an inhibitory activity on PARP. the following compound is known.
compound (1): 4-(2-acetyloxyphenyl)-2H-phthalazin-1-one (CAS Registry No. 71271-37-9).
Energetic investigations have been carried out to find a compound having poly(ADP-ribose)polymerase inhibitory activity. As a result, the present inventor have found that these aims may be accomplished by a 2H-phthalazin-1-one derivatives of the formula (I).
The 2H-phthalazin-1-one derivatives of the formula (I) have not been known as poly(ADP-ribose)polymerase inhibitor at all. The 2H-phthalazin-1-one derivatives of the formula (Ia) are novel compounds, which have been unknown so far.
The present invention relates to
(1) Poly(ADP-ribose)polymerase inhibitors containing a 2H-phthalazin-1-one derivatives of the formula (I) 
wherein R1 is
(i) C1-4 alkyl substituted by hydroxy or amino, or
(ii) xe2x80x94A1xe2x80x94A2xe2x80x94A3,
in which A1 is
(i) xe2x80x94NR3C(O)xe2x80x94,
(ii) xe2x80x94NR4C(S)xe2x80x94,
(iii) xe2x80x94NR5SO2xe2x80x94,
(iv) xe2x80x94CH2xe2x80x94NR6xe2x80x94,
(v) xe2x80x94CH2xe2x80x94Oxe2x80x94,
(vi) xe2x80x94OC(O)xe2x80x94,
(vii) xe2x80x94CH2xe2x80x94NR7C(O)xe2x80x94,
(viii) xe2x80x94NR8C(O)NR9xe2x80x94,
(ix) xe2x80x94NR10C(O)Oxe2x80x94,
(x) xe2x80x94NR11C(S)NR12xe2x80x94,
(xi) xe2x80x94NR13xe2x80x94, or 
with the proviso that the linkage of the right side of each group represented by A1 binds to A2,
wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl,
A2 is
(i) C1-8 alkylene,
(ii) C2-8 alkenylene,
(iii) Cyc1,
(iv) xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94,
(v) xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94,
(vi) xe2x80x94(C1-4 alkylene)xe2x80x94NR16xe2x80x94(C1-4 alkylene)xe2x80x94,
(vii) xe2x80x94(Cyc1)xe2x80x94(C1-8 alkylene)xe2x80x94,
(viii) xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1)xe2x80x94, or
(ix) xe2x80x94(C1-4 alkylene)xe2x80x94(Cyc1)xe2x80x94(C1-4 alkylene),
R16 is a hydrogen atom, C1-8 alkyl, C1-8 alkoxycarbonyl, phenyl or C1-8 alkyl substituted by phenyl,
Cyc1 is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
A3 is
(i) a hydrogen atom,
(ii) xe2x80x94NR17R18,
(iii) Cyc2,
(iv) xe2x80x94OR19,
(v) xe2x80x94COOR20,
(vi) xe2x80x94CONR21R22,
(vii) Cxe2x89xa1N,
(viii) a halogen atom, 
R17, R21 and R22 each, independently, is
(i) a hydrogen atom,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc3,
(vi) C1-8 alkoxy,
(vii) C2-8 alkenyloxy,
(viii) C2-8 alkynyloxy, or
(ix) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, 1-8 alkylthio, CN, hydroxy or 1-3 of halogen atom,
R18 is
(i) a hydrogen atom,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) C1-8 alkoxycarbonyl,
(vi) C2-8 acyl,
(vii) C3-8 cycloalkyl,
(viii) C1-8 alkoxycarbonyl substituted by Cyc3 or 1-3 of halogen atom, or
(ix) C1-8 alkyl substituted by C1-8 alkoxy,
R19 and R20 each, independently, is a hydrogen atom or C1-8 alkyl,
R23, R24, R25, R26, R27, R28 and R29 each, independently, is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, phenyl, or C1-4 alkyl substituted by phenyl,
Cyc2 is a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
Cyc1 is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom, the above-mentioned Cyc1, Cyc2 and Cyc3 each, independently, may be optionally substituted by 1-3 of substituents selected from the following (i)-(vii):
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) C1-8 alkoxy,
(v) C1-8 alkoxycarbonyl,
(vi) oxo, or
(vii) C1-8 alkyl substituted by C1-8 alkoxy;
R2 is a hydrogen atom, a halogen atom, nitro, hydroxy, xe2x80x94NR30R31, C1-8 alkyl, C1xcx9c8 alkoxy, or
C1-8 alkyl or C1-8 alkoxy substituted by 1-3 of halogen atoms,
R30 and R31 each, independently, is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, phenyl, C1-4 alkyl substituted by phenyl,
with the proviso that, R1 is not dimethylamino,
or a non-toxic salts as active ingredient.
(2) A 2H-phthalazin-1-one derivatives of the formula (Ia) 
wherein R1a is
(i) C1-4 alkyl substituted by hydroxy or amino, or
(ii) xe2x80x94A1axe2x80x94A2axe2x80x94A3a,
in which A1a is
(i) xe2x80x94NR3aC(O)
(ii) xe2x80x94NR4aC(S)xe2x80x94,
(iii) xe2x80x94NR5aSO2xe2x80x94,
(iv) CH2xe2x80x94NR6axe2x80x94,
(v) xe2x80x94CH2xe2x80x94Oxe2x80x94,
(vi) xe2x80x94OC(O)xe2x80x94,
(vii) xe2x80x94CH2xe2x80x94NR7aC(O)xe2x80x94,
(viii) xe2x80x94NR8aC(O)NR9axe2x80x94,
(ix) xe2x80x94NR10aC(O)Oxe2x80x94,
(x) xe2x80x94NR11aC(S)NR12axe2x80x94,
(xi) xe2x80x94NR13axe2x80x94, or 
with the proviso that the linkage of the right side of each group represented by A1a binds to A2a,
wherein R3a, R4a, R5a, R6a, R7a, R8a, R9a, R10a, R11a, R12a, R13a, R14a and R15a each independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl,
A2a is
(i) C1-8 alkylene,
(ii) C2-8 alkenylene,
(iii) Cyc1a,
(iv) xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94,
(v) xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94,
(vi) xe2x80x94(C1-4 alkylene)-NR16axe2x80x94(C1-4 alkylene)xe2x80x94,
(vii) xe2x80x94(Cyc1a)xe2x80x94(C1-8 alkylene)xe2x80x94,
(viii) xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1a)xe2x80x94, or
(ix) xe2x80x94(C1-4 alkylene)xe2x80x94(Cyc1a)xe2x80x94(C1-4 alkylene),
R16a is a hydrogen atom, C1-8 alkyl, C1-8 alkoxycarbonyl, phenyl or C1-8 alkyl substituted by phenyl,
Cyc1a is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
A3a is
(i) a hydrogen atom,
(ii) NR17aR18a,
(iii) Cyc2a,
(iv) xe2x80x94OR19a,
(v) xe2x80x94COOR20a,
(vi) xe2x80x94CONR21aR22a,
(vii) Cxe2x89xa1N,
(viii) a halogen atom, 
R17a, R21a and R22a each, independently, is
(i) a hydrogen atom,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc3a,
(vi) C1-8 alkoxy,
(vii) C2-8 alkenyloxy,
(viii) C2-8 alkynyloxy, or
(ix) C1-8 alkyl substituted by Cyc3a, C1-8 alkoxy, C1-8 alkylthio, CN, hydroxy or 1-3 of halogen atom,
R18a is
(i) a hydrogen atom,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) C1-8 alkoxycarbonyl,
(vi) C2-8 acyl,
(vii) C3-8 cycloalkyl,
(viii) C1-8 alkoxycarbonyl substituted by Cyc3a or 1-3 of halogen atom, or
(ix) C1-8 alkyl substituted by C1-8 alkoxy,
R19a and R20a each, independently, is a hydrogen atom or C1-8 alkyl,
R23a, R24a, R25a, R26a, R27a, R28a and R29a each, independently, is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, phenyl, or C1-4 alkyl substituted by phenyl,
Cyc2a is a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
Cyc3a is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
the above-mentioned Cyc1a, Cyc2a and Cyc3a each, independently, may be optionally substituted by 1-3 of substituents selected from the following (i)-(vii):
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) C1-8 alkoxy,
(v) C1-8 alkoxycarbonyl,
(vi) oxo, or
(vii) C1-8 alkyl substituted by C1-8 alkoxy;
R2a is a hydrogen atom, a halogen atom, nitro, hydroxy, xe2x80x94NR30aR31a, C1-8 alkyl C1xcx9c8 alkoxy, or C1-8 alkyl or C1-8 alkoxy substituted by 1-3 of halogen atoms,
R30a and R31a each, independently, is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, phenyl, C1-4 alkyl substituted by phenyl,
with the proviso that, R1a is not dimethylamino, 4-(2-acetyloxyphenyl)-2H-phthalazin-1-one is excluded],
or a non-toxic salt thereof.
(3) A compound of the formula (Ia) described in the above-mentioned (2),
in which R1 has the same meaning as hereinbefore (2),
R16a is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, phenyl, or C1-4 alkyl substituted by phenyl,
Cyc1a is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, one oxygen atoms and/or one sulfur atom, and Cyc1a may be substituted by C1-8 alkoxycarbonyl,
A3a is
(i) a hydrogen atom,
(ii) xe2x80x94NR17aR18a,
(iii) Cyc2a,
(iv) xe2x80x94OR19a,
(v) xe2x80x94COOR20a,
(vi) xe2x80x94CONR21aR22a, 
R17a, R21a and R22a each, independently, is a hydrogen atom, C1-4 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,
R18a is a hydrogen atom, C1-4 alkyl, C1-8 alkoxycarbonyl, C2-5 acyl, or C1-4 alkoxycarbonyl substituted by phenyl,
R19a and R20a each, independently, is a hydrogen atom or C1-4 alkyl,
Cyc2a is a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, one oxygen atoms and/or one sulfur atom, substituted by C1-8 alkoxycarbonyl,
R2a is a hydrogen atom, a halogen atom, nitro, or NR30aR31a.
(4) A compound of the formula (Ia) described in the above-mentioned (2)
wherein
R1a is xe2x80x94A1axe2x80x94A2axe2x80x94A3a,
A1a and A2a is the same meaning as hereinbefore (2),
A3a is (ii) xe2x80x94NR17aR18a, (iii) Cyc2a, (vii) xe2x80x94Cxe2x89xa1N, or (viii) a halogen atom, with the
proviso that, when A3a is NR17aR18a, then R17a represents the groups except a hydrogen atom, C1-4 alkyl, phenyl, or C1-4 alkyl substituted by phenyl in the above-mentioned (2), Cyc2a is a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom, substituted by 1-3 of substituent selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, oxo, or C1-8 alkyl substituted by C1-8 alkoxy (with the proviso that when the substituent is selected from C1-8 alkyl, C1-8 alkoxy, or C1-8 alkyl substituted by C1-8 alkoxy, then the number of the substituent is 2 or 3).
(5) A compound of the formula (Ia) described in above-mentioned (2)
wherein,
R2a is hydroxy, C1-8 alkyl, C1-8 alkoxy, or
C1-8 alkyl or C1-8 alkoxy substituted by 1-3 of halogen, and
(6) The process for the preparation of the novel 2H-phthalazin-1-one derivatives of the formula (Ia), or a non-toxic salts thereof.
Unless othewise specified, all isomers are included in the present invention.
For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include straight and branched isomers.
Isomers in the double bonds, rings, fused rings (E, Z, cis, trans isomers), isomers generated by the existence of asymmetric carbon atom(s) (R, S isome, xcex1,xcex2 isomers, enantiomers, diastereomers), optically active isomers having optically rotatory power (D, L, d, l isomers), polar isomers separated by chromatography (more polar, less polar isomers), equilibrium compounds, arbitrary, ratios of these compounds, racemic mixtures are all included in the present invention.
Optically active isomers of formula (I) and (Ia) may be obtained by general methods of optically separation (for example, separation by gas chromatography or high performance liquid chromatography, separation by crystallization as diastereomeric salts or clathrates, separation by prior crystallization etc.) or may be prepared by general methods of asymmetric synthesis.
In the present invention, C1-4 alkyl means methyl, ethyl, propyl, butyl and isomers thereof.
C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
C2-8 alkenyl means ethenyl, propenyl, butenyl, pentenyl, hexenyl, eptenyl, octenyl and isomers thereof.
C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.
C1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and isomers thereof.
C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
C2-8 alkenyloxy means ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy and isomers thereof.
C2-8 alkynyloxy means ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy and isomers thereof.
C1-8 alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomers thereof.
C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
C2-8 acyl means acetyl, propionyl, butyryl, valery, hexanoyl, heptanoyl, octanoyl and isomers thereof.
C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
C1-8 alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio and isomers thereof.
C3-10 membered mono- or bicarbocyclic ring means, for example,
(1) C3-10 cycloalkyl, cycloalkenyl, cycloalkanediene and cycloalkanetriene, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene, cycloheptatriene, cyclooctatriene, cyclononatriene, cyclodecatriene,
(2) C6-10 aromatic carbocyclic ring such as benzene, pentalene, indan, indene, naphthalene, azulene,
(3) perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, etc.
a 3-10 membered mono-cyclic or bi-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom includes a 3-10 membered mono-cyclic or bi-cyclic hetero aryl, partially saturated or fully saturated hetero aryl containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom.
Above-mentioned 3-10 membered mono-cyclic or bi-cyclic hetero aryl ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiin (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, carbazole, acridine, etc.
Above-mentioned 3-10 membered mono-cyclic or bi-cyclic partially saturated or fully saturated hetero aryl containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom means, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetraazoline, tetraazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiine (dihydrothiopyran), tetrahydrothiine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothi ophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzoth iadiazepine, benzazepine, benzodiazepine, indoloxazepine, indolotetrahydrooxazepine, indolooxadiazepine, indolotetrahydrooxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, 1,3-dioxoindane, 1,4-benzodioxane, quinuclidine, aziridine, dioxane, oxirane, thioxirane, azetidine, oxetane, thioxetane, etc.
Above-mentioned 3-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms and/or one oxygen atom means, for example, aziridine, azetidine, pyrrole, pyrroline, pyrrolidine, piperidine, pyridine, dihydropyridine, tetrahydropyridine, azepine, dihydroazepine, tetrahydroazepine, perhydroazepine, oxirane, oxetane, fu ran, dihydrofu ran, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, oxepi n, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, piperazine, dehydropiperadine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, pyrazine, dihydropyrazine, tetrahydropyrazine, pyridazine, dihydropyridazine, tetrahydropyridazine, diazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, morpholine, oxazole, isoxazole, oxazine, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, oxazepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, oxadiazole, dihydrooxadiazole, perhydrooxadiazole, isoxadiazole, dihydroisoxadiazole, perhydroisoxadiazole, oxadiazine dihydrooxadiazine, perhydrooxadiazine, oxadiazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, etc.
A halogen atom is chlorine, bromine, fluorine or iodine.
In the compound of formula (I), R1 is preferably xe2x80x94A1xe2x80x94A2xe2x80x94A3.
A1 is preferably xe2x80x94NR3C(O)xe2x80x94, xe2x80x94NR4C(S)xe2x80x94, xe2x80x94NR5SO2xe2x80x94, xe2x80x94NR8C(O)NR9xe2x80x94 or xe2x80x94NR10C(O)Oxe2x80x94, more preferably xe2x80x94NR3C(O) or xe2x80x94NR5SO2xe2x80x94, even more preferably xe2x80x94NR3C(O)xe2x80x94, and most preferably xe2x80x94NHC(O)xe2x80x94.
A2 is preferably C1-8 alkylene, C2-8 alkenylene, xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94NR16xe2x80x94(C1-4 alkylene)xe2x80x94 or xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1)xe2x80x94, more preferably C1-8 alkylene, C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94 or xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1)xe2x80x94, and most preferably C3-4 alkylene.
A3 is preferably OR19, NR17R18 or Cyc2, and more preferably Cyc2.
Cyc1 and Cyc2 are preferably 3-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms and/or one oxygen atom, for example, pyridine, pyrrole, pyrazine, pyrimidine, pyridazine, azepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, morpholine, etc.
Cyc1 is preferably 3-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, for example, pyridine, pyrrole, pyrazine, pyrimidine, pyridazine, azepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, etc.
Cyc2 is preferably 3-7 membered mono-cyclic hetero ring containing one nitrogen atom and one oxygen atom, for example, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, morpholine, etc., and most preferably morpholine.
Cyc3 is preferably C3-10 membered mono-carbocyclic ring or 3-7 membered mono-cyclic hetero ring containing 1-2 nitorogen atoms and/or one oxygen atom, for example, C3-10 cycloalkyl, cycloalkenyl, cycloalkanediene and cycloalkanetriene such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene, cycloheptatriene, cyclooctatriene, cyclononatriene, cyclodecatriene, benzene, pyridine,pyrrole, pyrazine, pyrimidine, pyridazine, azepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, morpholine, etc.
In the compound of formula (I), R2 is preferably a hydrogen atom, a halogen atom, nitro, NR30R31 or trifluoromethyl, more preferably a hydrogen atom, a halogen atom or trifluoromethyl, and most preferably a hydrogen atom.
In the compound of formula (I), R1a is preferably xe2x80x94A1axe2x80x94A2axe2x80x94A3a.
A1a is preferably xe2x80x94NR3aC(O)xe2x80x94, xe2x80x94NR4aC(S), xe2x80x94NR5aSO2, NR8aC(O)NR9axe2x80x94 or xe2x80x94NR10aC(O)Oxe2x80x94, more preferably xe2x80x94NR3aC(O)xe2x80x94 or xe2x80x94NR5aSO2xe2x80x94, even more preferably xe2x80x94NR3aC(O)xe2x80x94, and most preferably xe2x80x94NHC(O)xe2x80x94.
A2a is preferably C1-8 alkylene, C2-8 alkenylene, xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94NR16axe2x80x94(C1-4 alkylene)xe2x80x94 or or xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1a)xe2x80x94, more preferably C1-8 alkylene, xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94 or xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1a)xe2x80x94, and most preferably C3-4 alkylene.
A3a is preferably OR19a, NR17aR18a or Cyc2a, and more preferably Cyc2.
Cyc1a and Cyc2a is preferably 3-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms and/or one oxygen atom, for example, pyridine, pyrrole, pyrazine, pyrimidine, pyridazine, azepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, morpholine, etc.
Cyc1a is preferably 3-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, for example, pyridine, pyrrole, pyrazine, pyrimidine, pyridazine, zepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, etc.
Cyc2a is preferably 3-7 membered mono-cyclic hetero ring containing one nitrogen atom and one oxygen atom, for example, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, morp holine, etc., and most preferably morpholine.
Cyc3a is preferably C3-10 mono-carbocyclic ring or mono-cyclic hetero ring containing 1-2 nitrogen atoms and/or one oxygen atom, for example, C3-10 cycloalkyl, cycloalkenyl, cycloalkanediene and cycloalkanetriene such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene, cycloheptatriene, cyclooctatriene, cyclononatriene, cyclodecatriene, benzene, pyridine, pyrrole, pyrazine, pyrimidine, pyridazine, azepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, tetrahydropyridine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydroazepine, tetrahydroazepine, perhydroazepine, hexahydropyrimidine, morpholine, etc.
In the compound of formula (I), R2a is preferably a hydrogen atom, a halogen atom, nitro, NR30aR31a or trifluoromethyl, more preferably a hydrogen atom, a halogen atom or trifluoromethyl, and most preferably a hydrogen atom.
Non-toxic salts of the present invention include all pharmaceutically acceptable salts, for example, general salts, acid addition salts, hydrate salts.
The compounds of formulae (I) and (Ia) of the present invention may be converted into the corresponding salts by conventional method. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include:
salts of alkali metals (e.g. potassium, sodium, etc.), salts of alkaline earth metals (e.g. calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine, etc.).
The compounds of formulae (I) and (Ia) of the present invention may be converted into the corresponding acid addition salts by conventional method. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include:
salts of inorganic acid e.g. hydrochloride, hydrobromide, sulfate, phosphate, nitrate; or salts of organic acids e.g. acetate, trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.
The compounds of formulae (I) and (Ia) of the present invention and salts thereof may be converted into the corresponding hydrates by conventional means.
In the compounds of the present invention of formula (I), the compound of the formula (I-A) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-B) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-C) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-D) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-E) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-F) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-G) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-H) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-J) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-K) 
wherein all symbols are the same meaning as hereinbefore defined,
the formula (I-M) 
wherein all symbols are the same meaning as hereinbefore defined, or
the formula (I-N) 
wherein all symbols are the same meaning as hereinbefore defined are preferably.
The preferred specific compounds are the compounds in following tables 1-27, the compounds described in the examples and non-toxic salts thereof.
In the following tables, Me is methyl group and the other symbols are the same meaning as hereinbefore defined.
The compounds of formula (I) of the present invention may be prepared by following, described in example or known methods.
[1] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR3C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94NR7C(O), that is the compounds of the formula (I-1) 
wherein A1-1 is xe2x80x94NR3C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94NR7C(O)xe2x80x94, A2-1, A3-1 and R2-1 are the same meaning as A2, A3 and R2 respectively, with the proviso that the amino group included in the group represented by A2-1 is protected if necessary, xe2x80x94COOH, hydroxy, amino, amidino or guanidino group included in the group represented by A3-1 is protected if necessary, the amino group included in the group represented by R2-1 is protected if necessary, protective group for xe2x80x94COOH means, for example, methyl, ethyl, t-butyl, benzyl, etc., protective group for hydroxy means, for example, methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc., protective group for amino means, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, etc., the other symbols are the same meaning as hereinbefore defined
may be prepared by amidation of the compound of the formula (II) 
wherein Y1 is xe2x80x94NHR3 or xe2x80x94CH2xe2x80x94NHR7, the other symbols are the same meaning as hereinbefore defined
with the compound of the formula (III)
HOOCxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(III)
wherein all symbols are the same meaning as hereinbefore defined.
The amidation is known per se and can be carried out by methods for example:
(1) using an acid halide,
(2) using a mixed acid anhydride,
(3) using a condensing agent, etc.
These methods are explained as follows.
1) The method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (oxalyl chloride or thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
2) The method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (pivaloyl chloride, tosyl chloride or mesyl chloride, etc.) or an acid derivative (ethyl chloroformate or isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C., and then by reacting the mixture of acid anhydride obtained with a corresponding amine in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
3) The method using a condensing agent (1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyidiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide, etc.) may be carried out, for example, by reacting a carboxylic acid with a corresponding amine using a condensing agent in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, dimethyl formamide or diethyl ether, etc.) or without a solvent, in the presence or absence of 1-hydroxybenztriazole (HOBt) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
These reactions 1), 2) and 3) hereinbefore described may be, preferably carried out in an atmosphere of inert gas (argon or nitrogen, etc.) under anhydrous conditions.
[2] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR5SO2xe2x80x94, that is the compounds of the formula (I-2) 
wherein A1-2 is xe2x80x94NR5SO2xe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by sulfonamidation of the compound of the formula (IV) 
wherein all symbols are the same meaning as hereinbefore defined
with the compound of the formula (V) 
wherein X is a halogen atom, the other symbols are the same meaning as hereinbefore defined.
The sulfonamidation is known per se and can be carried out in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
[3] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94OC(O)xe2x80x94, that is the compounds of the formula (I-3) 
wherein A1-3 is xe2x80x94OC(O)xe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by esterification of the compound of the formula (VI) 
wherein all symbols are the same meaning as hereinbefore defined
with the compound of the formula (III) hereinbefore described
HOOCxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(III)
wherein all symbols are the same meaning as hereinbefore defined.
The esterification is known per se and can be carried out by methods for example:
1) using an acid halide,
2) using a mixed acid anhydride,
3) using a condensing agent, etc.
These methods are explained as follows.
1) The method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (oxalyl chloride or thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding alcohol in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
2) The method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (pivaloyl chloride, tosyl chloride or mesyl chloride, etc.) or an acid derivative (ethyl chloroformate or isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C., and then by reacting the mixture of acid anhydride obtained with a corresponding alcohol in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
3) The method using a condensing agent (1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide, etc.) may be carried out, for example, by reacting a carboxylic acid with a corresponding alcohol using a condensing agent in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, dimethyl formamide or diethyl ether, etc.) or without a solvent, in the presence or absence of 1-hydroxybenztriazole (HOBt) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
These reactions 1), 2) and 3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (argon or nitrogen, etc.) under anhydrous conditions.
[4] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94CH2xe2x80x94Oxe2x80x94, that is the compounds of the formula (I-4) 
wherein A1-4 is xe2x80x94CH2xe2x80x94Oxe2x80x94, the other symbols are the same meaning as hereinbefore defined
(a) may be prepared by etherification of the compound of the formula (VII-a) 
wherein Y2 is xe2x80x94CH2xe2x80x94OH, the other symbols are the same meaning as hereinbefore defined
with the compound of the formula (VIII-a)
R32A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(VIII-a)
wherein R32 is leaving group (for example, a halogen atom, mesyl or tosyl, etc.), the other symbols are the same meaning as hereinbefore defined,
(b) may be prepared by etherification of the compound of the formula (VII-b) 
wherein Y3 is xe2x80x94CH2xe2x80x94R32, the other symbols are the same meaning as hereinbefore defined
with the compound of the formula (VIII-b)
HOxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(VIII-b)
wherein all the symbols are the same meaning as hereinbefore defined, or
(c) may be prepared by etherication of the compound of the formula (VII-a) hereinbefore described with the compound of the formula (VIII-b) hereinbefore described.
The etherication of a compound of formula (VII-a) and a compound of formula (VIII-a), and a compound of formula (VII-b) and a compound of formula (VIII-b) is known per se and can be carried out, for example, in an inert organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) using hydroxide of alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 100xc2x0 C.
The etherication of a compound of formula (VII-a) and a compound of formula (VII-a), and a compound of formula (VII-b) and a compound of formula (VIII-b) is known per se and can be carried out, for example, in an organic solvent (dichloromethane, ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of azo compound (azodicarboxylic acid diethyl, azodicarboxylic acid diisopropyl, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) with a corresponding alcohol compound at a temperature of from 0xc2x0 C. to 60xc2x0 C.
[5] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR13xe2x80x94, that is the compounds of the formula (I-5) 
wherein A1-5 is xe2x80x94NR13xe2x80x94, the other symbols are the same meaning as hereinbefore defined
(a) may be prepared by reacting the compound of the formula (IV) hereinbefore described with the compound of the formula (IX)
Y4xe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(IX)
wherein Y4 is leaving group (for example, a halogen atom, etc.), the other symbols are the same meaning as hereinbefore defined, or
(b) the compound of the formula (X) 
wherein all symbols are the same meaning as hereinbefore defined
with the compound of the formula (XI)
R13HNxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(XI)
wherein all symbols are the same meaning as hereinbefore defined.
The reaction of the compound of the formula (IV) with the compound of the formula (IX) and the reaction of the compound of the formula (X) with the compound of the formula (XI) are known per se and can be carried out in the presence or absence of a base (triethylamine, pyridine, etc.) in an inert organic solvent (dimethyl formamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
(c) In the compounds of formula (I-5) of the present invention, the compound in which A2-1 is C1-8 alkylene, C2-8 alkenylene, xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94NR14xe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1)xe2x80x94, or xe2x80x94(C1-4 alkylene)xe2x80x94(Cyc1)xe2x80x94(C1-4 alkylene), that is the compounds of the formula (I-5xe2x80x2) 
wherein A2-1 is C1-8 alkylene, C2-8 alkenylene, xe2x80x94(C1-4 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-4 alkylene)xe2x80x94NR14xe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-8 alkylene)xe2x80x94(Cyc1), or xe2x80x94(C1-4 alkylene)xe2x80x94(Cyc1)xe2x80x94(C1-4 alkylene), the other symbols are the same meaning as hereinbefore defined
may be prepared by reductive amination of the compound of the formula (IV)
hereinbefore described with the compound of the formula (XI)
OHCxe2x80x94A2-1xe2x80x3xe2x80x94A3-1xe2x80x83xe2x80x83(XII)
wherein A2-1xe2x80x3 is C1-7 alkylene, C2-7 alkenylene, xe2x80x94(C1-3 alkylene)xe2x80x94Oxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-3 alkylene)xe2x80x94Sxe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-3 alkylene)xe2x80x94NR14xe2x80x94(C1-4 alkylene)xe2x80x94, xe2x80x94(C1-7 alkylene)xe2x80x94(Cyc1)xe2x80x94, or xe2x80x94C1-3 alkylene)xe2x80x94(Cyc1)xe2x80x94(C1-4 alkylene)xe2x80x94, the other symbols are the same meaning as hereinbefore defined.
The reductive amination is known per se and can be carried out, for example, in an organic solvent (methanol, ethanol, etc.), using reductive agent (sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, etc.), if necessary, in the presence of an acid (acetic acid, hydrochloric acid, etc.) at a temperature of from xe2x88x9220xc2x0 C. to 60xc2x0 C.
[6] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94CH2xe2x80x94NR6xe2x80x94, that is the compounds of the formula (I-6) 
wherein A1-6 is xe2x80x94CH2xe2x80x94NR6xe2x80x94, the other symbols are the same meaning as hereinbefore defined
(a) may be prepared by reacting the compound of the formula (XIII) 
wherein all symbols are the same meaning as hereinbefore defined
with the compound of the formula (IX) hereinbefore described,
(b) may be prepared by reacting the compound of the formula (X) hereinbefore described with the compound of the formula (XIV)
Y4xe2x80x94CH2xe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(XIV)
wherein all symbols are the same meaning as hereinbefore defined, or
(c) may be prepared by reductive amination of the compound of the formula (XV) 
wherein all symbols are the same meaning as hereinbefore defined with the compound of the formula (XI) hereinbefore described.
The reaction of the compound of the formula (XIII) with the compound of the formula (IX) and the reaction of the compound of the formula (X) with the compound of the formula (XIV) are known per se and can be carried out by the same method as the reaction of the compound of the formula (IV) hereinbefore described and the compound of the formula (IX).
The reductive amination of the compound of the formula (XV) with the compound of the formula (XI) can be carried out by the same method as the reaction of the compound of the formula (IV) hereinbefore described and the compound of the formula (XII).
[7] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR8C(O)NR9xe2x80x94, that is the compounds of the formula (I-7) 
wherein A1-7 is xe2x80x94NR8C(O)NR9xe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (IV) hereinbefore described with the compound of the formula (XVI)
Oxe2x95x90Cxe2x95x90Nxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(XVI)
wherein all symbols are the same meaning as hereinbefore defined.
The reaction is known per se and can be carried out in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
[8] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR11C(S)NR12xe2x80x94, that is the compounds of the formula (I-8) 
wherein A1-7 is xe2x80x94NR11C(S)NR12xe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (IV) hereinbefore described with the compound of the formula (XVII)
Sxe2x95x90Cxe2x95x90Nxe2x80x94A2-1xe2x80x94A3-1xe2x80x83xe2x80x83(XVII)
wherein all symbols are the same meaning as hereinbefore defined.
The reaction can be carried out by the same method as the reaction of the compound of the formula (IV) hereinbefore described and the compound of the formula (XVI).
[9] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR10OC(O)Oxe2x80x94, that is the compounds of the formula (I-9) 
wherein A1-9 is xe2x80x94NR10OC(O)Oxe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (IV) hereinbefore described with the compound of the formula (XVIII) 
wherein all symbols are the same meaning as hereinbefore defined.
The reaction is known per se and can be carried out, for example, in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, etc.) at a temperature of from xe2x88x9278xc2x0 C. to 40xc2x0 C.
[10] In the compounds of formula (I) of the present invention, the compound in which A1 is xe2x80x94NR4C(S)xe2x80x94, that is the compounds of the formula (I-10) 
wherein A1-10 is xe2x80x94NR4C(S)xe2x80x94, the other symbols are the same meaning as hereinbefore defined
may be prepared by thiocarbonylation of the compound of the formula (I-1xe2x80x2) 
wherein A1-1xe2x80x2 is xe2x80x94NR3C(O)xe2x80x94, the other symbols are the same meaning as hereinbefore defined.
The reaction is known per se and can be carried out in an organic solvent (dioxane, benzene, toluene, xylene, tetrahydrofuran, etc.), using Lawesson""s reagent at a temperature of from 20xc2x0 C. to 150xc2x0 C.
[11] In the compounds of formula (I) of the present invention, the compound in
which A1 is 
that is the compounds of the formula (I-11) 
wherein A1-11 is 
the other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (IV) hereinbefore described with the compound of the formula (XIX) 
wherein Y5 is C1-4 alkyl, the other symbols are the same meaning as hereinbefore defined.
The reaction is known per se and can be carried out, for example, in an organic solvent (methanol, ethanol, etc.) at a temperature of from 0xc2x0 C. to 50xc2x0 C.
[12] In the compounds of formula (I) of the present invention, the compound in which A3 is xe2x80x94NR17R18 or hetero ring as shown by 
wherein the ring represents Cyc2, which comprises at least one nitrogen atom (the nitrogen atom is connected to A2),
that is the compounds of the formula (I-12) 
wherein A3 is xe2x80x94NR17R18 or hetero ring as show 
the other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (I-12xe2x80x2) 
wherein all symbols are the same meaning as hereinbefore defined
with the compound of the formula (XX)
Hxe2x80x94NR17R18xe2x80x83xe2x80x83(XX)
wherein all symbols are the same meaning as hereinbefore defined, or
the compound of the formula (YY) 
wherein all symbols are the same meaning as hereinbefore defined.
The reaction of the compound of the formula (I-12xe2x80x2) with the compound of the formula (XX) or the compound of the formula (YY) may be carried out by the same method as [5] (a) hereinbefore described.
[13] In the compounds of formula (I) of the present invention, the compound wherein at least one of A2, A3 or R2 is xe2x80x94COOH, hydroxy, amino, amidino guanidino, or a group including xe2x80x94COOH, hydroxy, amino, amidino or guanidino, that is the compounds of the formula (I-13) 
wherein A2-2, A3-2 or R2-2 are the same meaning as A2, A3 or R2, with the proviso that at least one of A2, A3 or R2 is xe2x80x94COOH, hydroxy, amino, amidino, guanidino, or the group including xe2x80x94COOH, hydroxy, amino, amidino or guanidino, and the other symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound of the formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11) and (I-12) hereinbefore described by alkali hydrolysis, deprotection reaction under acidic conditions, deprotection reaction of silyl group or deprotection reaction by hydrogenation.
Deprotection reaction by alkali hydrolysis is known, for example, it is carried out in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Deprotection reaction under acidic conditions is known, for example, it is carried out in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.), in organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acid-acetic acid etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
Deprotection reaction of silyl group is known, for example, it is carried out in a water-soluble organic solvent (tetrahydrofuran, acetonitrile, etc.), using tetrabutylammonium fluoride at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Deprotection reaction by hydrogenation is known, for example, it is carried out in an inert solvent [ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), ketone (e.g. acetone, methylethylketone, etc.), nitrile (e.g. acetonitrile etc.), amide (e.g. dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof], in the presence of hydrogenating catalyst (e.g. palladium-carbon, palladium black, palladium, palladium hydroxide, platinum hydroxide, platinum dioxide, nickel, Raney-nickel, ruthenium chloride, etc.) in the presence or absence of inorganic acid (e.g. hydrochloric acid, sulfuric acid, hypochlorous acid, boronic acid, tetrafluoroboronic acid, etc.) or organic acid (e.g. acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid etc.), under normal atmosphere or suppressed atmosphere of hydrogen or in the presence of ammonium formate, at a temperature of from 0xc2x0 C. to 200xc2x0 C. In use of acid, its salt may be used.
In the present invention deprotection reaction means a comprehensive deprotection reaction easily understood by those skilled in the art, for example, alkali hydrolysis, deprotection reaction under acidic condition, deprotection reaction by hydrogenation. The desired compounds of the present invention can be easily prepared by these reactions.
As should be easily understood by those skilled in the art, methyl, ethyl, t-butyl and benzyl are included in the protective groups for carboxyl, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl and benzyl are included in the protective groups for hydroxy, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Benzyloxycarbonyl, t-butoxycarbonyl and trifluoroacetyl are included in the protective groups for amino, amidino and guanidino but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
The compounds of formula (II), (III), (IV), (V), (VI), (VII-a), (VII-b), (VIII-a), (VIII-b), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX) are known per se or may be easily prepared by known methods.
For example, the compounds of formula (XIX) may be prepared by the method described in the following reaction schemes. 
The all symbols in the reaction schemes are as hereinbefore described.
The compounds of the formula (XX) in the reaction schemes are known per se or may be prepared by known methods.
In each reaction described in the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions.
It has been confirmed that the compounds of the present invention of the formula (I) possess an inhibitory activity against PARP by the following experimental results.
1) Enzyme Assay In Vitro
Methods
The below procedure was carried out with 96 well plate. The reaction mixture contained 50 mM Tris/HCl (pH 8.0, WAKO), 10 mM MgCl2, 5 mM dithiothreitol (sigma), and 0.5 mg/mL activated DNA in 80 xcexcL. The 10 xcexcL of test compound was added to the reaction mixture and the reaction was started by addition of 10 xcexcL of 0.01 xcexcL PARP (TREVIGEN). The reaction was terminated at 10 minutes by addition of 100 xcexcL of 20% trichloroacetic acid. The reaction product was collected on a glass fiber filter (GF/C, PACKARD). The radioactivity was measured by topcount (PACKARD). Inhibitory activity of the compound was represented by 50% inhibitory concentration (IC50) calculated 100% of control (distilled water). The results were shown in Table 28.
2) Ischemia-reperfusion Injury Model (Brain and Heart)
Model of cerebral or coronary ischemia-reperfusion was prepared according to procedures described previously (Jpn. J. Stroke, 8, 1 (1986), Stroke, 27, 1624-1628 (1996) and Eur. J. Pharmacol., 270, 45 (1994)). This invention compound was effective in ischemia-reperfusion injury model.
Toxicity
The toxicity of the compounds of the present invention is very low and therefore compounds may be considered safe for pharmaceutical use.
Inhibition of PARP is useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis or arthritis etc.), neurodegenerative disorders (extrapyramidal disease, Alzheimer""s disease or muscular dystrophy etc.), diabetes, shock, head trauma, reanal insufficiency or hyperalgesia etc. Also it is increased the effects of antiretroviral (HIV etc.) or anticancer drugs.
For the purpose above described, the compounds of formula (I) of the present invention and non-toxic salts thereof, acid addition salts thereof and hydrates thereof may normally be administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered as inner solid compositions or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules etc. Capsules contain hard capsules and soft capsules.
In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, xcexccrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate etc.), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, suspensions, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavouring agents, perfuming agents, preserving agents and buffer agents etc.
Injections for parenteral administration include solutions, suspensions and emulsions and solid injections which are dissolved or suspended in solvent when it is used. One or more active compound(s) is or are dissolved, suspended or emulsified in a solvent when such compositions are used. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution, plant oil, propylene glycol, polyethylene glycol and alcohol such as ethanol etc., and mixture thereof. Such compositions may comprise additional diluents such as stabilizing agent, assisting agents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark) etc.), suspending agents, emulsifying agents, dispersing agents, buffer agents, preserving agents etc. They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, ointments, endermic liniments, aerosols, spray compositions, suppositories and pessaries for vaginal administration etc. which comprise one or more of the active compound(s) and may be prepared by known methods.
Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.